Basic ethers of the pyridine series



Patented Oct. 4, 1932 UNITED STATES, PATENT ormcs KARL MIESCHE'R AND ERNEST canon, or BASEL, SWITZERLAND, nssrenons r THE FIRM SOCIETY OF CHEMICAL INDUSTRY IN BASLE, 0F IBASEL, SWITZERLAND m ETHEBS 01* 'rHErYa'rbmE seems No Drawing, Application filed July 28; 1930, Serial No. 471,4 15,and'in'Switzcrland August 10, 1929.

, The present invention relates to new basic ethers of the pyridine series useful in v therapeutics.

It has been found that basic ethers ofthe pyridine series are obtained by causing rebinds acids.

active esters of amino-alcohols to act on hydroxy-pyridines or thejnuclear substitutionproduots thereof,or amino-alcohols to .act on halogen-pyridines orthe substitution products thereof, or amlnes to act on halogenalkoxy pyridines or the substitution products thereof. These reactions arecarried out preferably in presenceof an agent that 'Asoreactive estersof amino-alcohols may be used, for example, aminoa'lkylesters or hydrohalogenie acids or of aromatic sulfo acids. 7 v I The new bases combine withacids'to salts soluble in water. They may be employed'a's such or as intermediate products for thera peutical purposes.

The following examples illustrate the invention, the parts beingby weight I r lk-solution of 2.8:fpar ts rof'lsodium in80 lated. The 2- diethylaminoethoxypyridine of the formula thus obtained is a colorless oil of boiling point 98V100 at 2 mm. pressure.- .It is sparnew base is iso are heatedin a solution of toluene with 70 parts of chlorethyldiethylamine until the reaction is complete. The solvent is expelled and the 2 diethylaminoethoxypyridine sepa rated from the NEdiethyl-aminoethyl-2-pyridine simultaneously formed by. fractionating'. It shows the same properties as indicated in Example 1. 7

Example 3 t 27 parts of2-chloro 3-pyridine-carboxylic acid-phenetidide are added-t0 a solution of 2.6 parts of sodium in an excess of diethylaminoethanol and the mixture is heated on the oil-bath. After the separation of the sodium chloride, the excess of the base is distilled off, the residue dissolved in ether, the solution filtered, and the ether expelled. The remaining 2-diethylaininoethoxy-3-pyridinecarbo'xylic acid-phenetidide of the formula oo-mnOo-oim is recrystallized from petroleum ether. It is obtainedincolorless crystals melting at 63"v C. The monohydrochloride melts at 163 C. It is easily soluble in water. a

The 2-chloro-3epyridine-carboxylic acid-. phentidide of melting point 115 C. is obtained bycausing phenetidine to react on 2-chloro-3=pyridine-carboxylic acid-chloride.

The 2-chloro-3-pyridine-carboxylic acid-chloride is formed by treatment of one molecular lo-om-onhmoinm I y proportion of 2- hydroxy-3-pyridine-carboxylic acid with 2 molecular proportions of phosphorous pentachloride. It forms colorless crystals. The melting point is 56 C. and the boiling point 98-400 C. at 2 mm. pressure; r '1 Ewample 4 2.8 parts of sodium dissolved in an excess of aminoethanol and 23 parts of 2-chloro-3a pyridine-carboxylic acid-anilide are heated on the oil-bath. After separation of the sodium chloride, the excess of aminoethanol is distilled off. The residue is taken up in ethyl i a o pyridine thus forme d of the formula.

precipitated asmonohydrochloride means of alcoholic hydrochloric acid. It forms White crystals of meltingpoint 203 C. and is easily-soluble in Water; 1

may he obtained by the reaction of 2 -chloro-3- pyridine-carboxylic acid-chloride on aniline:

It forms colorless crystals of melting-point V e pulyerised sodium,f120 parts of diethyl'am'inoethanol' and 5 00 partsof toluene are heated on the Water-bathuntilall sodium: is 'dissolved. After addition of 113.5 grams of.4 -chlor,opyric lille, the Whole is' boi'led for somejhours in a reflux apparatus. The. cooled toluene solution is extracted with dilute hydrochloric acid and fromlthe aqueoussolution'the net base is precipitated by means. of

a caustic soda solution, {It is takenup in ether, dried with potassium: carbonate and, afterevapora'tionof the ether, distilled in high 'Vacuum. The 3 l-diethylaminoethoxy- 2.8 parts of sodium dissolved in an excess 7 of diethylaminoethanol, and-23 parts of 2 chloro-5spyridine-carboxylio aoid-anilide' are heated on an oil-loath. 'After separation of the sodium chloride the excess of diethylaminoethanolis distilled off. The residue is recrystallized from 'ligroine. There is'th-us obtained: the 2-.diethylaminoethoxy-5 pyridine-carboxylic aoid-anilide of the formula P The 2-chloro-5-pyridine oarlooxylic acidanilide is obtained by causing 2-chloro-5-pyridine-carboxylic acid-chloride to react with aniline, It forms colorless crystals'of melting point 171%172 Ct;

I chloride is formed'hy the interactionof 2 molecularproportions of phosphorous pentaf The 2 chloro-5-pyridine-carboxylic acids formula 4 boils at 95 C. at 0.03 mm. pressure. It forms I \V melting point 133 7 2-ldiethylaminoethoxy-. 3 -;pyridine carhydroxy-5-pyridine-carboxylic acid. It as tils at 859 C. at 3 mm. pressure and forms colorless crystals of melting point 49-51 C.,

Ewample .7 I

7 7V um chloridetheexcess ofthebaseis distilled 2-chloro-3-pyrid'ne-carhoXylio acid -anilide The residue is extracted with anhydrous alcohol. After evaporation of the alcohol the 2; (hl hyd ffilxyethylaminoethoxy) -3-pyridinecarboxylic acid-anilide of the formula p is 7 obtained as a yellowish" oil, "easily solu ble-incol d, hut With difiicultysol-ulole in Warm Water-.- 7 The piorate- 20 -208 sodium: chloride the toluene isdistill'ed off,

The residue isextraotedfwith;benzene" From the benzolic solution the amino-di (2-ethoXy 3zpyridine-carboxylic o ajcid-anilide) of the crystallizes out; forming colorless crystals of Ina similar manner there can be obtained, for instancef'the followmg compounds:-

Melting point 2 dimethylaminoethoxy-3=pyridine-car- I o V bo yhc-aeid-anilide monohydrochlo-V L V ride: colorless crystals 20s? 52-. Il -butylam;inoethoxy 3 pyridinea c arhoxyl-io acid 7 anilide monohydrochloride: colorless crystals "11 23? 2 piperidinoethoxy- 3 -pyridine-carlooX- ylic-acidanilide-monohydrochloride colorless crystals 2 diethylaminoethoxy-3 pyridine carboxylic-acid-N-ethylanilide-monohydrochloride colorless crystals 2% dieth'ylaminoethoxy 3': pyridine car-1 'boxylic-aciddiethylethylenediamidee dihydrochloride' colorless, crystals;

" loox ylio v ac idiedietliylaminoethanoles-' of the lease melts at ter-dihydrochloride: colorless'orystals 2 diethylaminoethoxy 7 3; pyridine carlooXylio-aoideanilide-monohydrochlo- I iri'de gcolorlesserystals;;;; 112

The free base of the last compound forms a yellowish oil, insoluble in water, soluble in organic solvents and in dilute mineral acids.

What we claim is: 1. Basic ethers of the general formula wherein one of the As means a group of the formula i R meaning an alkylene radical containing at least two carbon atoms, and R and R hydrogen or alkyl, R or R alsohydroXyalkyl,

and the other As mean hydrogen or a carboxylic amide gro-upsubstituted by phenyl, alkyl or diethylaminoethyl, which products form with acids water-soluble salts, and are useful in therapeutics.

2; Basic ethers of thegeneral formula:

R meaning an alkylene radical containing at least two carbon atoms, and R and R hydrogen or alkyl, R or R also hydroxyalkyl, and one of the As standing'for hydro gen, and'the other for hydrogen or a carboXylic. amide group substituted by phenyl,

alkyl or diethylaminoethyl, which products form with acids water-soluble salts, and are useful in. therapeutics. I

3. Basic ethers of the general formula R meaning an alkylene radical containing 7 i at least two carbon atoms, and R and R y g y R1 or R also hydroxyalkyl, and A standing for hydrogen or a e' carboXylic amide group substituted by' phenyl, alkyl or diethylaminoethyl, "which 7 products form with acids water-soluble salts,

and are useful in therapeutics. V 1. Basic ethers of the general formula R andR meaning hydrogen or alkyl, R

or R also hydroxyalkyl, and A standing for a carboxylic. amide group substituted by .phenyl, alkyl or diethylaminoethyl, which products form with acids Water-soluble salts, I

and are useful in therapeutics.

5. Basic ethers of the general formula 02115 O-OHr-GHz-N N CzH5 A standing for a carboxylic amide group substituted by phenyl, alkyl or diethylaminoethyl, which products form with acids watersoluble salts, and are useful in therapeutics. 6. The 2 diethylaminoethoxy- 3 pyridine carboxylic acid-anilide of the formula 02H; forming a yellowish oil insoluble in water,

[soluble in organic solvents and in dilute mineral acid, its monohydrochloride melting at 17 2 (3., which product is useful in therapeutics or as an intermediate product.

7. The basic ethers of the general formula V R1 L ooH2omN R R and R meaning hydrogen, alkyl, or hydroxyalkyl, which products form with acids water-soluble salts, and are useful in therapeutics.

8. The 2-diethylaminoethoxy-pyridine of the formula O H H /C2H5 N/- C 2-0 2N\ forming a colorless oil of boiling point 98- 100 C. at 2 mm. pressure, sparingly soluble in water, but easily in organic solvents and acids, its mono-hydrochloride melting at 0., which product is useful in therapeutics or 

